Current management of adrenal tumors Rajesh Kuruba and Scott F. Gallagher
University of South Florida College of Medicine, USF Health and Tampa General Hospital, Florida, USA
Correspondence to Scott F. Gallagher, MD, FACS, Assistant Professor of Surgery, University of South Florida College of Medicine, USF Health, c/o Tampa General Hospital, Suite F-145, 2 Columbia Drive, Tampa, FL 33601, USA Tel: +1 813 844 7473; fax: +1 813 844 1920; e-mail: sgallagh@health.usf.edu
Current Opinion in Oncology 2008, 20:34-46
Purpose of review
Adrenal tumors evoke considerable interest and diagnostic challenges. This rare group of tumors includes functional tumors with a gamut of clinical presentations, as well as adrenocortical carcinoma, with its advanced disease at presentation and dismal prognosis posing additional challenge. Increasing detection of incidentalomas adds further interest with the concomitant diagnostic and management dilemmas.
Recent findings
Significant advances have been made in diagnostic imaging modalities for identifying malignancy risk in adrenal incidentalomas. Considerable progress has occurred in understanding adrenocortical carcinoma pathogenesis from the study of genetics at the germline level in familial carcinomas, as well as at the somatic level by analyzing molecular alterations in sporadic tumors; this research supplies opportunities to develop novel therapeutic agents against a tumor with poor prognosis.
Summary
Laparoscopic adrenalectomy has emerged as standard of care in the treatment of functional benign adenomas and nonfunctional tumors larger than 4 cm when adrenocortical carcinoma is not suspected. Open adrenalectomy with en-bloc excision has been the mainstay for primary and recurrent adrenocortical carcinoma due to the lack of effective adjuvant therapy. International consensus conferences have attempted to standardize diagnostic and treatment approaches in the management of adrenal tumors; further research is necessary.
Keywords
adrenal incidentaloma, adrenal tumors, adrenocortical carcinoma, Cushing’s syndrome, mitotane, pheochromocytoma
Curr Opin Oncol 20:34-46 @ 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8746
Introduction
Adrenal masses are among the most common tumors, found in at least 3% of people (>50 years) in autopsy studies. Most are nonfunctional and only 1 in 4000 is malignant [1]. Adrenal tumors can be stratified into adrenal medullary and adrenocortical tumors. The aim of this review is to summarize recent advances in biochemical, genetic, and radiological diagnosis while emphasizing current management options.
Adrenal medullary tumors
Adrenal medullary tumors include pheochromocytomas, as well as rare ganglioneuromas, ganglioneuroblastomas, and neuroblastomas; the latter are predominantly child- hood tumors and not reviewed here. Pheochromocy- tomas are catecholamine-producing, neuroendocrine tumors arising from chromaffin cells in the adrenal medulla, as defined by the 2004 World Health Organiza- tion (WHO) classification [2]. The estimated incidences in the general population (0.005-0.1%) and in the adult hypertensive population (0.1-0.2%) account annually 1040-8746 @ 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
for 3-4 diagnoses/million in the US [3]. Recent studies have challenged the 10% rule - estimated incidence of hereditary predisposition is 20-30%, whereas the preva- lence of extra-adrenal tumors can reach 23% [4 ** ,5,6 ** ]. In multiple endocrine neoplasia type 2 and von Hippel- Lindau syndrome, prevalence of bilateral tumors can be higher. The prevalence of malignancy in extra-adrenal pheochromocytomas is ~33% and can be even higher in certain familial paragangliomas (SDHB gene mutations, see later) [7,8].
Since the clinical presentation varies, with similar signs and symptoms as many other clinical conditions, a 3-year mean diagnostic delay exists between initial presentation and definitive diagnosis [9,10]. With increasing utilization of imaging studies, approximately 25% of pheochromo- cytomas are diagnosed incidentally [9]. Advances in genetics have identified germline mutations for familial pheochromocytomas in five genes (Table 1): the von Hippel-Lindau gene (VHL), the RET gene, the neurofi- bromatosis type 1 gene (NF1), and succinate dehydro- genase subunits B and D genes (SDHB and SDHD).
| Gene | Disease | Age range (years) | Features | Chromosome | Protein | Germline mutations in apparent sporadic pheochromocytoma | Catecholamine type | Extra-adrenal disease | Malignancy |
|---|---|---|---|---|---|---|---|---|---|
| VHL | von Hippel-Lindau disease | 5-49 | Hemangioblastomas, (spinal cord, brain, retina), renal, pancreatic, endolymphatic sac tumors, pheochromocytoma (10-20%) | 3p25-26 | pVHL19 and VHL30 | 2-11% | NE | þ | 5% |
| RET | Multiple endocrine neoplasia type 2 | 18-50 | Medullary carcinoma thyroid, ganglioneuromas, hyperparathyroidism, pheochromocytoma (40-50%) | 10q11.2 | Tyrosine-kinase receptor | <5% | E | 3% | |
| NF1 | Neurofibromatosis | 25-69 | Neurofibromatosis, Lisch nodules, Schwannomas, gliomas, mengiomas, pheochromocytoma (<5%) | 17q11.2 | Neuro-fibromin | Unknown | E | þ | 11% |
| SDHB | Familial paraganglioma syndrome | 10-58 | Head and neck paragangliomas, abdominal or thoracic paragangliomas | 1p36.13 | Catalytic iron-sulfur protein | 3-10% | Unknown | ++ | 66-83% |
| SDHD | Familial paraganglioma syndrome | 5-65 | Head and neck paragangliomas, abdominal or throracic paragangliomas | 11q23 | CybS (membrane- spanning subunit) | 4-7% | Unknown | ++ | <3% |
Tumor catecholamine phenotypes are designated as either epinephrine-producing (E) or predominantly norepinephrine-producing (NE). ++; +; - , Relative likelihoods of adrenal or extra-adrenal disease from high to low. Reproduced from [6 ** ,8,27].
Mutation testing is now available for four of these (RET, VHL, SDHB, and SDHD). Guidelines from the recent international consensus conference recommend genetic testing should be used judiciously after a complete work- up, specialized genetic consultation, and informed con- sent in the following situations: family history or younger than 50 years old (VHL, RET, SDHB and SDHD genes), multiple tumors (SDHB, SDHD and VHL genes), malig- nant tumors (SDHB and VHL genes), and bilateral tumors (RET, VHL and SDHD genes) [4 ** ].
Diagnostic confirmation of pheochromocytoma requires biochemical evidence of inappropriate catecholamine production, and measurement of vanillylmandelic acid (VMA) with urinary and plasma catecholamines has traditionally been used. As pheochromocytomas secrete catecholamines episodically but metabolize them con- tinuously, recent studies suggest that measurement of plasma and urinary fractionated free metanephrines (i.e. normetanephrine and metanephrine measured separ- ately) provides superior diagnostic capability [4 ** ,8,11]. False-positive results can arise from dietary or drug interferences and inappropriate sampling conditions; a clonidine suppression test can be used to distinguish falsely positive increased catecholamines from those due to sympathetic activation from pheochromocytoma [12].
Due to similar sensitivities (90-100%) and specificities (70-80%), there is no consensus on whether computed tomography (CT) or MRI is preferred for initial localization of a tumor, except in pregnant women, children and patients with contrast allergies when MRI is preferred [4 ** ,13]. On MRI, most pheochromo- cytomas are hypointense on T1-weighted images and markedly hyperintense on T2-weighted images (Fig. 1). Adrenal venous sampling for elevated catecholamines or metanephrines can be helpful when conventional imaging studies fail to localize the pheochromocytoma.
Functional imaging with 123I-meta-iodobenzylguanide (MIBG) scintigraphy can be used to distinguish pheochro- mocytomas or paragangliomas (95-100% specificity) but sensitivity is low. MIBG-scintigraphy is useful for deter- mining the extent of disease for patients with increased risk of malignancy (extra-adrenal or >5 cm tumors) and for patients with biochemical evidence of pheochromocytoma in whom CT/MRI have failed to identify the tumor(s) [14 ** ,15,16]. Radio-labeled octreotide (Octreoscan) and analogs have better efficacy in imaging extra-adrenal and metastatic pheochromocytoma than intra-adrenal pheochromocytoma. Other options include PET imaging with nonspecific ligand 18F-fluorodeoxyglucose (18F-FDG PET) and specific ligands like [18F]-dihydroxyphenyla- lanine, [11C]-hydroxyephedrine, or [11C]-epinephrine, and 6-[18F]-fluorodopamine [17*].
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Current recommendations for imaging pheochromocyto- mas include, first, anatomic imaging to assess tumor size, vascular invasion, and local invasion, and second, functional imaging to detect metastatic disease [17°]. Octreoscan and PET imaging modalities are reserved for patients with negative 123I-labeled MIBG scintigra- phy or rapidly growing tumors with high metabolic rates or tumors expressing somatostatin receptors rather than initial localization [13,18]. One recent study evaluated 14 patients with suspected pheochromocytoma (8 con- firmed pheochromocytomas) using MIBG scintigraphy, PET with18F-FDG (FDG PET), and [11C]-metahydrox- yephedrine (mHED-PET scan) ligands; mHED-PET identified all confirmed sites; FDG PET successfully localized all sites of adrenal and metastatic disease except bony metastasis, and MIBG failed to detect one or more sites of confirmed pheochromocytoma [18].
Surgical resection is definitive treatment for pheochro- mocytoma. Historically, preoperative treatment with @-adrenoceptor preceding ß-adrenoceptor antagonists with increased salt and fluid intake for volume expansion has reduced perioperative mortality to less than 3% [19]. Alternatively, the use of preoperative calcium channel blockers allows control of hypertension preoperatively, minimizes perioperative/intraoperative blood-pressure fluctuations, and facilitates rapid medication discontinu- ation postoperatively.
With decreased pain, shorter hospitalization and less recovery time, as well as improved patient satisfaction compared with open adrenalectomy, laparoscopic adrenalectomy is the preferred approach for benign functioning and nonfunctioning tumors (<12cm) of the adrenal gland. In a recent literature review (338 patients), laparoscopic adrenalectomy cured 98% of pheochromocytomas with resolution or significant improvement of hypertension [20°].
Any evidence of malignancy (i.e. local invasion) should prompt hand-assisted or open adrenalectomy, due to
increased risk of tumor fragmentation and technical difficulty in removing these tumors laparoscopically [21,22]. Compared with sporadic pheochromocytoma, recurrent pheochromocytoma (Fig. 2) occurs more commonly in patients with extra-adrenal disease (33% compared with 14%) and familial pheochromocytoma (33% compared with 13%) [23]. With the high incidence of bilaterality in familial pheochromocytoma (Fig. 3), adrenal-cortical-sparing partial adrenalectomy has been advocated to minimize adrenal insufficiency, possibly obviating life-long glucocorticoid supplementation [24,25]. This must be weighed against the risk of tumor recurrence ipsilaterally (10%) and contralaterally (30%) following partial adrenalectomy [23,24]. Annual follow- up is indicated for all pheochromocytomas and should be continued indefinitely with extra-adrenal or familial pheochromocytoma for early detection of recurrences.
Malignant pheochromocytoma
No histological features, including capsular or vascular invasion and cytologic atypia, can predict or provide unequivocal evidence of malignant potential. Only metastasis establishes malignancy definitively; the most common metastatic sites are bones, lungs, liver, and lymph nodes. Depending on tumor site and genetic predisposi- tion, incidence of metastatic pheochromocytoma (3-36%) and 5-year survival rate (34-60%) vary - patients with skeletal metastases have longer survival than patients with liver and lung metastases [4 ** ,26,27]. The rate of malignancy is increased for large tumors (>5 cm, 76% compared with 24% in tumors ≤5cm), extra-adrenal tumors (36%), patients with SDHB mutations (66- 83%), and increased plasma or urinary concentrations of dopamine and norepinephrine [5,27-29].
Dopamine production, representing more premature catecholamine secretion, is predictive of malignancy. Patients with malignant pheochromocytoma have higher plasma or urinary norepinephrine and are noted to have significantly shorter metastasis-free intervals [29].
Figure 2 Images of pheochromocytoma
The computed tomography topogram (top left) shows multiple clips above each kidney consistent with the history of prior open left adrenalectomy and laparoscopic right adrenalectomy. The sagittal image (top right) shows a 2-cm, subtle, enhancing mass medial to the superior pole of the left kidney, inferior to the IVC and most of the prior clips; this mass is more conspicuous using multiplanar reconstruction than on a previous standard computed tomograph. The bottom left sagittal image shows the same mass (white arrow) with the corresponding coronal image (bottom right) with the left pheochromocytoma (white arrow); this can be compared with the topogram (top left).
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Multifactorial analyses have helped to identify tumors with metastatic risk, and various scoring systems have been proposed; however, there has been no consensus on these systems [30,31].
While there is no effective treatment for malignant pheochromocytoma, radical debulking is the mainstay for symptomatic improvement without proven survival advantage. External-beam irradiation for skeletal metas- tasis and radiofrequency ablation can be used for palliation or debulking [4 ** ,32]. Combination chemotherapy (cyclo- phosphamide, vincristin, and dacarbazine) can provide short-term remission (50%) [33]. As the single-most valuable adjunct after surgical debulking, 131I-MIBG therapy provides symptomatic relief in most (80%), but remission is rare (5% complete, 30% partial) [8,34].
Not all patients with malignant pheochromocytomas have sufficient MIBG (Fig. 4) uptake to allow 131MIBG therapy. In-vitro studies have suggested treatment with cytotoxic chemotherapeutic agents may increase uptake of MIBG in neuroendocrine tumor cells; a recent study showed an additive effect with combination 131I-MIBG and chemotherapy (n=6, enrollment halted for toxicity pending further controlled studies) [35].
Adrenocortical tumors
Adrenocortical tumors include benign adenomas, myelo- lipomas, and malignant adrenocortical carcinoma (ACC) (Figs 5 and 6). Both benign and malignant tumors may be functional, producing excess of cortisol, aldosterone or sex-steroids leading to Cushing’s syndrome, Conn’s
Figure 3 Images of pheochromocytoma
The CT topogram (top left) shows multiple clips from prior open left adrenalectomy and laparoscopic right adrenalectomy in the same patient as in Fig. 2, which highlights the increased likelihood of extra-adrenal pheochromocytoma in hereditary syndromes; the line corresponds to the sagittal section (top right), which shows a 2.5-cm, subtle, enhancing mass (white arrow) anterior and superior to the left renal vein. The sagittal image (bottom left) shows the same mass (white arrow); the line corresponds to the coronal image (bottom right) with the left pheochromocytoma; note the clips from the previous operations, which highlights the high incidence of bilateral disease in familial pheochromocytoma.
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After 361 µCi of 1-131, meta-iodobenzylguanide (MIBG) scan shows two anterior projections with gray arrows indicating a focal area of abnormal increased uptake of I-131 MIBG in the right abdomen, con- sistent with the inferior, recurrent pheochromocytoma. The posterior views show increased activity in this region as well as a second area of increased activity just superior, also to the right of the midline, consistent with recurrent pheochromocytomas, corresponding to the CT scans in Figs 2 and 3.
syndrome or hirsutism/virilization, respectively. Cortisol- producing tumors (Fig. 7) and aldosteronomas (Fig. 8) are usually associated with benign adenomas, while virilizing tumors are more likely to be malignant adrenocortical carcinomas.
Benign adrenocortical tumors increase in prevalence with age and are detected in 3-7% of adults (>50 years old) [36]. The incidence of Cushing’s syndrome varies from 0.7 to 2.4/million population/year, in conjunction with adrenal adenoma (10%) and carcinoma (5%) [37]. Aldosterone-producing adrenocortical adenoma and carcinoma compose 30% and 1% of primary hyperaldos- teronism [38].
ACC accounts for 0.02% of all reported cancers and 0.2% of cancer-related deaths annually. Incidence of ACC is unusually high in southern Brazil where 3.4-4.2 diag- noses/million children compare with a worldwide inci- dence of 0.3 diagnoses/million children (<15 years old) [39]. ACC is more common in females (65-90% of reported patients) and is bilateral (2-10%) with a bimodal age distribution (first peak in children <5 years; the second peak in the 4th and 5th decades).
Advances have been made in understanding the molecular mechanisms responsible for rare genetic, familial, and
sporadic adrenocortical tumors [40,41 ** ]. Genetic altera- tions found in familial adrenocortical tumors include mutations of TP53 (17q13) gene in Li-Fraumeni syndrome, Menin (11q13) gene in multiple endocrine neoplasia type 1, PRKARIA (17q22-24) gene in Carney complex, and p57kip2 (CDKN1C), KCNQ10T, H19, IGF-II overexpression in Beckwith-Wiedemann syndrome. Menin gene mutations, TP53 somatic mutations, and CYP21 gene mutation are others found in sporadic adrenocortical tumors.
Functional adrenocortical tumors usually present with clinical features of endocrine syndromes (hormonal excess). Due to improved hormonal assay sensitivities, the frequency of functional adrenocortical tumors in recent series is up to 79% compared with 50% previously reported [41 ** ,42]. Cushing’s syndrome and hyperaldosteronism are the most common functional adrenocortical tumors in adults; Cushing’s syndrome is present in 30-40% of ACCs, suggested by cosecretion of androgens and cortisol [41 ** ].
Virilizing tumors are the most common functional adre- nocortical tumors in children, accounting for 20-30% of ACCs. Purely feminizing ACC is unusual. Nonfunctional ACC (60%) may present insidiously with weight loss and abdominal pain, and a palpable mass in about 50% of patients with metastatic disease is common (22-50%, Fig. 6) at presentation.
Patients with adrenal tumors should have hormonal evaluation for hypersecretion of cortisol, aldosterone, catecholamines, and sex steroids [4 ** ,37,38,43 ** ]. Adrenal scintigraphy, CT, MRI, and FDG-PET can localize adrenocortical tumors and predict malignancy. Current criteria suggesting benign adenoma include attenuation values, expressed as Hounsfield units (HU): fewer than 10 HU on unenhanced CT, fewer than 30 HU on enhanced scans with a 10-min delayed CT washout greater than 50%, and signal drop on out-of-phase chemical shift MRI. Tumors with more than 10 HU (hyperattenuating lesions) include lipid-poor adenomas (30% of all adenomas), pheochromocytomas, metastases, and ACC. Sensitivity and specificity for delayed, enhanced CT scan in diagnostic evaluation of hyperat- tenuating adrenal lesions are reported (92% and 98- 100%, respectively) [44]. There is no conclusive evidence that MRI is more sensitive in differentiating malignant from benign tumors. The only published report retro- spectively compared delayed, enhanced CT with chemi- cal shift MRI for hyperattenuating adrenal lesions (n=37 adenomas, n = 6 nonadenomas) [45°]. Delayed, enhanced CT characterized additional adrenal tumors more, with- out a significant difference in diagnostic accuracy.
Due to limited availability and unproven diagnostic utility, adrenal scintigraphy with NP-59 is seldom used.
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The CT scan shows enlargement of the left adrenal gland superiorly measuring 2.6 cm x 2.0 cm; it measures approximately 0 Hounsfield units (HU) on precontrast images (a) and enhances to 50-60 HU on postcontrast arterial image (b). Venous phase contrast is shown (c). These findings are nonspecific and could represent hyperplasia or adenoma, although neoplasm cannot be excluded.
In recent studies, FDG-PET appears to be useful in distinguishing adenomas from malignant tumors; PET using 11C-labeled metomidate, a tissue-specific imaging procedure, which binds to adrenal 11ß-hydroxylase, is an excellent tool to distinguish adrenocortical origin-adrenal adenomas and ACC from other lesions-especially characterizing potential metastases from ACC [41 ** ]. Fine-needle aspiration/biopsy of adrenal tumors is not recommended due to the risk of needle tract seeding, with limited diagnostic value differentiating benign from
malignant; it is (only after excluding pheochromocytoma) indicated for inoperable lesions prior to starting radiation or chemotherapy.
Malignancy risk is estimated in adrenocortical tumors on clinical (presentation and hormonal status), radiological (size), and histological criteria. Histopathology, immuno- histochemistry, and molecular techniques are useful in distinguishing adrenocortical adenomas from ACC. Several multiparameter histological scoring systems like
The CT scan shows a large, inhomogeneous adrenocortical carcinoma (large arrow) arising from the left adrenal gland; also shown are multiple hepatic and pulmonary metastases (small arrows).
Weiss, Weiss revisited index (WRI), and Van Slooten index (VSI) have been proposed to assess malignancy risk. Nuclear atypia, atypical and frequent mitoses (>5/50 high power fields), vascular and capsular invasion, and necrosis are suggestive of malignancy. Weiss score is most
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After 100c Isovue 370 nonionic contrast, a 3.3-cm, enhancing, right adrenal mass (arrow) is identified; the density of the mass is not specific for adrenal adenoma and is more consistent with adrenal neoplasm. Final pathology confirmed right adrenal cortisol-producing tumor (arrow) in a patient with Cushing’s syndrome.
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MRI of the abdomen shows a small mass (1 cm) involving the anterior limb of the left adrenal gland (arrow); it is isointense to the remaining adrenal on T2 weighted sequence and demonstrates significant dropout on the out-of-phase sequences. No abnormal enhancement was seen after Gadolinium; final pathology confirmed aldosteronoma.
widely used (range 0-9), but a score higher than 3 suggesting malignancy has limitations and is patho- logist-experience dependent. A recent study, comparing the prognostic value of WRI and VSI in 79 adrenal cortical tumors, found that both scoring systems have equal validity, correctly categorizing adenomas and ACC. Both indices correlated well with survival in metastatic ACC [46°]. Molecular markers like IGF-II overexpression and allelic losses at 17p13 with immunohistochemistry of Cyclin E or Ki-67 are potential tools to assess malignancy [41 ** ]. Until more data from large, prospective studies are available, routine use is currently not recommended [39].
Tumor staging is one of the most important prognostic factors in ACC. The 2004 TNM staging categories are stage I (<5 cm tumor), stage II (>5 cm tumor), stage III (locally invasive or regional lymph nodes metastasis), and stage IV tumors (metastatic tumors or invading adjacent organs) [47]. Likely due to improved and widespread use of imaging techniques resulting in earlier diagnosis and treatment, stage II tumors are more common in recent studies as compared with earlier studies when most patients presented with stage IV disease [47-50]. Prog- nosis is better in younger patients and for stage I and II tumors, whereas cortisol-secreting tumors are associated with worse prognosis [41 ** ].
Treatment of adrenocortical tumors
Laparoscopic adrenalectomy is indicated for functional and nonfunctional adenomas less than 12 cm [20°]. Almost all functional, benign adrenocortical tumors should be removed regardless of size, with only aldosteronomas continuing to be controversial with regard to predicting preoperatively which patients will experience resolution of signs and symptoms postoperatively. Laparoscopy is rela- tively contraindicated in benign tumors larger than 12 cm,
locally invasive tumors, and ACC; however, limits of safe laparoscopy continue to be tested [20°].
Open adrenalectomy with complete tumor extirpation by an experienced endocrine or oncologic surgeon in stage I-III ACC is the only chance to obtain long-term remission, with limited options for effective adjuvant treatment. En-bloc resection of locally invaded organs - kidney, liver, spleen, pancreas, and stomach - with regional lymphadenectomy should be done with extrac- tion of tumor thrombus from the inferior vena cava or renal vein, if present [47]. Stage IV functional tumors demon- strate improved prognosis along with palliation of symp- toms after tumor debulking with removal of the primary adrenal tumor. Figure 9 shows a management algorithm for ACC [47].
Adjuvant treatment of adrenocortical carcinoma
Radiotherapy, ‘adrenolytic’ treatment with mitotane, cytotoxic chemotherapy, and cytoreductive therapies (radiofrequency ablation and chemoembolization) have been used adjuvantly to improve local recurrence and survival rates or palliatively in metastatic ACC. Radiation is generally ineffective as treatment for ACC and is usually reserved for skeletal metastasis palliation to reduce pain or the risk of fractures [41 ** ]. A recent, retrospective, German series of adjuvant, tumor-bed irradiation (n=14) showed decreased 5-year recurrence from 79% to 12% without a change in overall or disease- free survival, likely related to the small sample size [51°].
Mitotane has been used with modest response (14-36%) in ACC [42]. In a multicenter, retrospective, European analysis, mitotane was administered adjuvantly to 47 Italian patients with ACC after radical surgery, which was compared with 55 Italian and 75 German patients without mitotane; patients receiving mitotane treatment showed 2-3 times longer recurrence-free survival [52°]. With mitotane’s narrow therapeutic index, treatment has marked toxicity with a daily dose of more than 6 gm; careful monitoring of serum levels is required. As mito- tane can induce adrenal insufficiency, patients may need glucocorticoid and mineralocorticoid supplementation during treatment.
Various chemotherapy regimens like the Berruti or Italian regimen (EDP/M, etoposide, doxorubicin, and platinum in combination with mitotane) and Khan regimen (Sz/M, streptozotocin plus mitotane) have been used adjuvantly, with partial response rates up to 50% [53,54]. An inter- national phase-III trial, First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT), comparing both regimens, is recruiting patients; however, it will take several years to accrue 300 patients.
ACC is resistant to chemotherapy as tumor cells express high levels of the multidrug-resistance protein (MDR1) or P-glycoprotein, which is encoded by the ABCB1 gene. Phase-II trials with MDRI efflux pump inhibitor (Tari- quidar), epidermal growth factor inhibitors (Gefitinib), anti-vascular-endothelial growth factor (Bevacizumab), and tyrosine kinase inhibitor (Sunitinib) are currently being conducted in patients with ACC. In a recent,
Figure 9 Management algorithm for adrenocortical carcinoma
EDP, etoposide, doxorubicin, cis-platin. a Adjuvant therapy should be considered for all patients at high risk for recurrence (tumor size>12 cm, high mitotic rate); b mitotane drug monitoring required; c after more than 2 years of complete remission, imaging intervals may be prolonged; d complete resection in stage IV should always be followed by adjuvant therapy; e after conference with the reference center. Reproduced with permission from [47].
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42 Endocrine tumors
nonrandomized, phase-II study, 15 adults unrespon- sive to conventional therapy with disseminated endo- crine tumors that expressed cell ligand receptor (c-kit) tyrosine kinase and platelet-derived growth factor recep- tor were treated with Gleevec (Imatinib mesylate); Gleevec did not appear useful and occasionally caused significant toxicity [55°].
Radiofrequency ablation of adrenal tumors from meta- static ACC, as well as liver and lung metastasis (<5 cm), is an alternative to surgical resection in patients with prohibitive surgical risk [56]. Chemoembolization has been used to treat recurrent and metastatic adrenocortical carcinoma in the liver [42].
Incidentalomas
An adrenal incidentaloma is defined as an adrenal mass, generally larger than 1 cm, discovered serendipitously during radiologic examination for indications other than evaluating adrenal disease [43 ** ,57]. Prevalence of adre- nal incidentalomas varies by age (0.2% in patients <30 years and 7% in patients >70 years), autopsy study (over- all 6%, range 1-32%), clinical setting (0.1% in patients screened with ultrasound for general health to 4.3% in patients with history of cancer), and diagnostic modality (4% with CT) [57-59]. Pathologic features of adrenal incidentalomas are summarized in Table 2. In patients with prior malignancy, most adrenal masses (75%) are metastatic compared with two-thirds that are benign in patients without a history of malignancy [1].
When evaluating adrenal incidentalomas, the diagnostic approach should include assessing hormonal status and malignant potential. In an unselected group of patients without endocrine-related symptoms, 70% of the inci- dentalomas were nonfunctional; approximately 5-20%
| Cause | Reported frequency (%) | Calculated frequency (%) |
|---|---|---|
| Adrenal cortical tumors | ||
| Adenoma | 36-94 | |
| Nonfunctioning | 7-94 | >80 |
| Cortisol-secreting | 0-12 | 0.035 |
| Aldosterone-secreting | 0-7 | 7.0 |
| Sex steroid-secreting | 0-11 | Rare |
| Nodular hyperplasia | 7-17 | |
| Adrenocortical carcinoma | 1.2-11 | 0.058 |
| Adrenal medullary tumors Pheochromocytoma | 1.5-11 | 6.5 |
| Other adrenal tumors | ||
| Myelolipoma | 7-15 | |
| Lipoma | 0-11 | |
| Cysts | 4-22 | |
| Hematoma | 0-4 | |
| Infections and granulomas | Rare | |
| Metastasis | 0-21 |
Reproduced from [1,36,58].
of patients had subclinical Cushing’s syndrome, 5% had pheochromocytomas, and 1% of patients had aldosterone- producing adenomas [43 ** ,60]. Sex hormone-secreting tumors are rare in the absence of hirsutism or virilization, so routine screening is not warranted. Careful history and physical examination focusing on adrenal hyperfunction is routine. Imaging evaluation has been done as outlined for adrenocortical tumors (Fig. 9).
It is estimated that the risk of malignancy is 2%, 6%, and 25% when adenoma size is smaller than 4 cm, 4-6 cm, and larger than 6cm, respectively [1]; the 2002 NIH consensus conference suggested surgical resection for nonfunctional incidentalomas larger than 6cm and observation for tumors smaller than 4 cm. Management of 4-6 cm nonfunctional incidentalomas remains contro- versial. One recent study comparing 457 patients with ACC with 47 patients with adenomas found that a size threshold of at least 4cm doubled the likelihood of malignancy to 10%; this further increased nine-fold for tumors larger than 8cm. As patients with ACC have better prognoses after early resection, recent studies suggest that surgical resection of incidentalomas at least 4 cm is warranted [43 ** ]. Our recent review of nearly 2000 adrenalectomies in Florida suggests that this practice is already occurring, since more benign adrenal tumors are being removed with increasing utilization of the laparoscopic approach and improved imaging modalities [61].
Image-guided needle biopsy (after excluding pheochro- mocytoma) should be reserved for differentiating adrenal from nonadrenal lesions (particularly related to diagnosing metastatic disease). Since cytologic distinction between adrenal adenomas and metastases is highly accurate but histologic distinction between benign adrenal and primary malignant adrenal lesions has less sensitivity (only 54- 86%), percutaneous aspiration biopsy is not recommended to differentiate adrenal adenoma from primary ACC.
Patients with hormonally active tumors (regardless of size), nonfunctional tumors (>4cm), and incidentalomas with suspicious features for malignancy (unenhanced CT attenuation >10 HU, CT contrast-media washout <50% and no signal drop on out-of-phase MRI) should undergo laparoscopic adrenalectomy. Any signs of local invasion or malignancy (metastasis or lymphadenopathy) should prompt hand-assisted or open adrenalectomy. While an algorithm for noninvasive imaging assessment of adrenal masses is not established, an algorithm for managing adrenal incidentalomas is proposed (Fig. 10).
Metastatic tumors
Lung, kidney, colon, breast, esophagus, pancreas, liver, and stomach are the most common sites of tumors
History & physical examination screening tests for hormonal excess
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Fat attenuation
Adrenalectomy
Observation (Lipid rich adenoma)
Observation (Myelolipoma)
Hyperattenuating lesions (Lipid poor adenoma, adrenocortical carcinoma, metastasis)
Repeat imaging 6,12, 24 months annual hormonal testing x 4 years
Delayed enhanced CT scan / chemical shift MRI
Hormonally active? Îsize > 1 cm / year?
No
> 50% contrast washout on CT signal drop on out- of- phase MRI
CT/MRI results
Yes
Adrenalectomy FNA if history of cancer or suspicion for infection
< 50% contrast washout on CT No signal drop on out-of-phase MRI
Adrenalectomy
metastasizing to adrenals (Fig. 11) [43 ** ]. Metastases are the cause of adrenal masses in 75% of patients with a history of malignancy and are frequently bilateral. 18F-FDG PET can be helpful in patients with a history of malignancy due to its high sensitivity, but 16% of benign adenomas may have increased uptake, limiting its utility [62].
Absence of activity on 11C-metomidate (MTO)-PET has been found to be specific for tumors of nonadrenocortical origin and is useful to exclude pheochromocytoma and metastatic disease; however, cost is often prohibitive [63°]. CT-guided and, more recently, EUS-guided nee- dle biopsy have been used to differentiate adrenal from nonadrenal tissues with acceptable complication rates [64,65].
Management of isolated adrenal metastases is contro- versial even after demonstrated safe resection by an
open or laparoscopic adrenalectomy with survival benefit. In carefully selected patients, particularly with long-term disease-free intervals, median survival ranges from 2 to 3.4 years. Patients with lung cancer and melanoma account for most reports [66]. A recent study of highly selected patients with adrenal metastasis from hepatocellular carcinoma showed an average survival longer than 2 years after resection [67]. Laparoscopic resection can be undertaken in carefully selected patients without local invasion. Adler et al. [68°] recently compared laparoscopic excision (n=17) to open adre- nalectomy (n=8) for metastases; they found no port site metastases, no local recurrences, and no difference in 5-year survival rates (during 97 months follow-up) [68*]. Suspicion of local invasion or ACC should prompt open adrenalectomy. There is currently no evidence supporting resection of adrenal metastasis of unknown origin.
44 Endocrine tumors
Figure 11 Enhancing, bilateral adrenal enlargement
Left adrenal measures 3.5 cm (arrow) and the right adrenal measures 3.1 cm, most likely consistent with bilateral adrenal metastases in this patient with prior left nephrectomy for renal cell carcinoma 6 years ago.
SCOUT Senes 201
FFS
614 x 512 x 16
AP SC WI Series 3
FFS
512 x 512 =16
20 cm
20 cm
L
0
AV 120
B
W 120
MA 50 TA : 0
Sice 0.75 Loch 149 9
W.300 L:500 HU
Tit : 0
Sice 3 Loc: 11.5
W. 400 L: 40 ML
MM47
COR AD
Inlance Tof
Series 804
512 x 15
5 MN DELAY Series 7
412 - 512 x 16
AC4
20 cm
20 cm
L
0
B
KV 120
9
14/ 120
mA 212
Conclusion
International consensus conferences have attempted to standardize the diagnostic and treatment approaches for adrenal tumors. Laparoscopic adrenalectomy has emerged as the standard of care to treat benign functional adenomas and nonfunctional tumors. Open adrenalect- omy with en-bloc excision is the mainstay for primary and recurrent ACC. Further investigation is necessary to determine optimal treatment for adrenal tumors and ACC, which may be improved through multi-institutional registries focused on developing effective adjuvant treat- ment strategies.
Acknowledgements
We would like to thank Dr Jeff Fabri for his critical review of the manuscript, and his insight and support. We would also like to thank Krista Haines, MABMH and Eric Wilson, BS for their assistance with the figures, and Dr Katie Carpenter for her assistance with the radiographic images.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
· of special interest
·· of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 122-123).
1 NIH state-of-the-science statement on management of the clinically inappar- ent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements 2002; 19:1-25.
2 DeLellis RA, Lloyd RV, Heitz PU, et al., editors. Pathology and genetics of tumours of endocrine organs. World Health Organization classification of tumors. Lyon: IARC Press; 2004.
3 Pederson LC, Lee JE. Pheochromocytoma. Curr Treat Options Oncol 2003; 4:329-337.
4 Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommenda-
.. tions for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 2007; 3:92-102.
Comprehensive review on the progress and recommendations for diagnosis, localization, and genetic testing for pheochromocytoma and its management.
5 Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003; 24:539-553.
6 Gimenez-Roqueplo AP, Lehnert H, Mannelli M, et al. Phaeochromocytoma,
.. new genes and screening strategies. Clin Endocrinol (Oxf) 2006; 65:699- 705.
This article reviews advances in genetics of pheochromocytoma and paraganglio- mas and proposes European guidelines and algorithm for genetic testing for pheochromocytoma.
7 Kaltsas GA, Papadogias D, Grossman AB. The clinical presentation (symp- toms and signs) of sporadic and familial chromaffin cell tumours (phaeochro- mocytomas and paragangliomas). Front Horm Res 2004; 31:61-75.
8 Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet 2005; 366:665-675.
9 Amar L, Servais A, Gimenez-Roqueplo AP, et al. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005; 90:2110-2116.
10 Mannelli M, Ianni L, Cilotti A, et al. Pheochromocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol 1999; 141:619-624.
11 Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheo- chromocytoma: which test is best? JAMA 2002; 287:1427-1434.
12 Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 2003; 88:2656-2666.
13 Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004; 89:479-491.
14 Lumachi F, Tregnaghi A, Zucchetta P, et al. Sensitivity and positive predictive
·· value of CT, MRI and 1231-MIBG scintigraphy in localizing pheochromocy- tomas: a prospective study. Nucl Med Commun 2006; 27:583-587.
Thirty-two consecutive patients with pheochromocytoma were evaluated with CT, MRI and MIBG scintigraphy. Sensitivity was 90%, 93% and 91% respectively, and the combination of MRI and MIBG scintigraphy had 100% sensitivity and positive predictive value.
15 van der Harst E, de Herder WW, Bruining HA, et al. [(123)[]metaiodoben- zylguanidine and [(111)In]octreotide uptake in benign and malignant pheo- chromocytomas. J Clin Endocrinol Metab 2001; 86:685-693.
16 Miskulin J, Shulkin BL, Doherty GM, et al. Is preoperative iodine 123 meta- iodobenzylguanidine scintigraphy routinely necessary before initial adrena- lectomy for pheochromocytoma? Surgery 2003; 134:918-922; discussion 922-923.
17 Gross MD, Avram A, Fig LM, et al. PET in the diagnostic evaluation of adrenal · tumors. Q. J Nucl Med Mol Imaging 2007; 51:272-283. Review article focusing on the role of PET imaging in various adrenocortical and adrenal medullary disorders.
18 Mann GN, Link JM, Pham P, et al. [11C]metahydroxyephedrine and [18F] fluorodeoxyglucose positron emission tomography improve clinical decision making in suspected pheochromocytoma. Ann Surg Oncol 2006; 13:187- 197.
19 Kinney MA, Warner ME, van Heerden JA, et al. Perianesthetic risks and outcomes of pheochromocytoma and paraganglioma resection. Anesth Analg 2000; 91:1118-1123.
20 Gumbs AA, Gagner M. Laparoscopic adrenalectomy. Best Pract Res Clin · Endocrinol Metab 2006; 20:483-499.
The authors critically review the benefits of laparoscopic adrenalectomy since its introduction and evaluate its effectiveness in the surgical management of endo- crine hypertension.
21 Walz MK, Peitgen K, Neumann HP, et al. Endoscopic treatment of solitary, bilateral, multiple, and recurrent pheochromocytomas and paragangliomas. World J Surg 2002; 26:1005-1012.
22 Li ML, Fitzgerald PA, Price DC, et al. latrogenic pheochromocytomatosis: a previously unreported result of laparoscopic adrenalectomy. Surgery 2001; 130:1072-1077.
23 Brunt LM, Lairmore TC, Doherty GM, et al. Adrenalectomy for familial pheochromocytoma in the laparoscopic era. Ann Surg 2002; 235:713- 720; discussion 720-721.
24 Yip L, Lee JE, Shapiro SE, et al. Surgical management of hereditary pheochromocytoma. J Am Coll Surg 2004; 198:525-534; discussion 534-535.
25 Brauckhoff M, Gimm O, Brauckhoff K, et al. Repeat adrenocortical-sparing adrenalectomy for recurrent hereditary pheochromocytoma. Surg Today 2004; 34:251-255.
26 Goldstein RE, O’Neill JA Jr, Holcomb GW 3rd, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg 1999; 229:755-764; discus- sion 764-766.
27 Eisenhofer G, Bornstein SR, Brouwers FM, et al. Malignant pheochromocy- toma: current status and initiatives for future progress. Endocr Relat Cancer 2004; 11:423-436.
28 O’Riordain DS, Young WF Jr, Grant CS, et al. Clinical spectrum and outcome of functional extraadrenal paraganglioma. World J Surg 1996; 20:916-921; discussion 922.
29 van der Harst E, de Herder WW, de Krijger RR, et al. The value of plasma markers for the clinical behaviour of phaeochromocytomas. Eur J Endocrinol 2002; 147:85-94.
30 Kimura N, Watanabe T, Noshiro T, et al. Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 2005; 16:23-32.
31 Linnoila RI, Keiser HR, Steinberg SM, et al. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 1990; 21:1168- 1180.
32 Mayo-Smith WW, Dupuy DE. Adrenal neoplasms: CT-guided radiofrequency ablation, preliminary results. Radiology 2004; 231:225-230.
33 Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988; 109:267-273.
34 Loh KC, Fitzgerald PA, Matthay KK, et al. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (1311-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 1997; 20:648-658.
35 Sisson JC, Shapiro B, Shulkin BL, et al. Treatment of malignant pheochro- mocytomas with 131-I metaiodobenzylguanidine and chemotherapy. Am J Clin Oncol 1999; 22:364-370.
36 Latronico AC, Chrousos GP. Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab 1997; 82:1317-1324.
37 Newell-Price J, Bertagna X, Grossman AB, et al. Cushing’s syndrome. Lancet 2006; 367:1605-1617.
38 Mattsson C, Young WF Jr. Primary aldosteronism: diagnostic and treatment strategies. Nat Clin Pract Nephrol 2006; 2:198-208; quiz, 1 p following 230.
39 Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 2005; 12:667-680.
40 Libe R, Bertherat J. Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 2005; 153:477-487.
41 Libe R, Fratticci A, Bertherat J. Adrenocortical cancer: pathophysiology and .. clinical management. Endocr Relat Cancer 2007; 14:13-28. This article reviews in detail the progress made during the last decade in under- standing the etiology of ACC at molecular level.
42 Roman S. Adrenocortical carcinoma. Curr Opin Oncol 2006; 18:36-42.
43 Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. .. N Engl J Med 2007; 356:601-610.
Comprehensive review on biochemical and radiological diagnosis of adrenal incidentalomas along with recommendations for their management.
44 Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002; 222:629-633.
45 Park BK, Kim CK, Kim B, et al. Comparison of delayed enhanced CT and
· chemical shift MR for evaluating hyperattenuating incidental adrenal masses. Radiology 2007; 243:760-765.
Authors compared delayed enhanced CT and chemical shift MRI in 37 adenomas and six nonadenomas retrospectively and found that delayed enhanced CT characterized five more adenomas and three more metastatic tumors than che- mical shift MR.
46 Van’t Sant HP, Bouvy ND, Kazemier G, et al. The prognostic value of two · different histopathological scoring systems for adrenocortical carcinomas. Histopathology 2007; 51:239-245.
Both Van Slooten Index and Weiss Revised Index had same diagnostic yield in characterizing malignancy risk in 79 adrenal cortical tumors; however, in case either of these scores yield equivocal results, authors suggested using both indices in assessing malignancy risk.
47 Allolio B, Fassnacht M. Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006; 91:2027-2037.
48 Kendrick ML, Lloyd R, Erickson L, et al. Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 2001; 136:543-549.
49 Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treat- ment with mitotane and a review of the literature. Cancer 1993; 72:3145- 3155.
50 Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Associa- tion of Endocrine Surgeons study group. World J Surg 2001; 25:891- 897.
51 Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the . tumor bed on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab 2006; 91:4501-4504.
This largest published series of adrenocortical cancer patients who received radiotherapy in adjuvant setting from German ACC registry found beneficial role for radiotherapy in reducing recurrence rates.
52 Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for · adrenocortical carcinoma. N Engl J Med 2007; 356:2372-2380. This retrospective large multicenter trial from Italy and Germany provides compel- ling evidence for use of mitotane in adjuvant setting for stage I, II and III ACC with complete macroscopic resection.
53 Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase Il trial. Endocr Relat Cancer 2005; 12:657-666.
54 Khan TS, Imam H, Juhlin C, et al. Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 2000; 11:1281-1287.
55 Gross DJ, Munter G, Bitan M, et al. The role of imatinib mesylate (Gleevec) for
· treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 2006; 13:535-540.
Pilot study investigating the role of Gleevec in c-kit and PDGF-R positive malignant endocrine tumors (including four patients with ACC) did not have beneficial effect in part due to early cessation of treatment secondary to high frequency of adverse effects.
56 Wood BJ, Abraham J, Hvizda JL, et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 2003; 97:554- 560.
57 Young WF Jr. Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000; 29:159- 185; x.
58 Kloos RT, Gross MD, Francis IR, et al. Incidentally discovered adrenal masses. Endocr Rev 1995; 16:460-484.
59 Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest 2006; 29:298-302.
60 Terzolo M, Bovio S, Reimondo G, et al. Subclinical Cushing’s syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am 2005; 34:423- 439; x.
61 Gallagher SF, Wahi M, Haines KL, et al. Trends in adrenalectomy rates, indications, and physician volume: A statewide analysis of 1816 adrenalec- tomies. Surgery (in press).
62 Yun M, Kim W, Alnafisi N, et al. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med 2001; 42:1795-1799.
46 Endocrine tumors
63 Hennings J, Lindhe O, Bergstrom M, et al. [11C]metomidate positron
· emission tomography of adrenocortical tumors in correlation with histopatho- logical findings. J Clin Endocrinol Metab 2006; 91:1410-1414.
In this retrospective study of 212 MTO-PET examinations in the management of adrenal tumors, authors found that this is a sensitive and specific study and also if the ratio of Standardized Uptake Value of hotspots (SUVhs) between the tumor and contralateral gland is > 1.4 this indicates 99.5% risk of adrenocortical tumor and if the SUVhs is >32 it indicates 95% risk of Conn’s adenoma.
64 Arellano RS, Harisinghani MG, Gervais DA, et al. Image-guided percutaneous biopsy of the adrenal gland: review of indications, technique, and complica- tions. Curr Probl Diagn Radiol 2003; 32:3-10.
65 DeWitt J, Alsatie M, LeBlanc J, et al. Endoscopic ultrasound-guided fine-needle aspiration of left adrenal gland masses. Endoscopy 2007; 39:65-71.
66 Mitchell IC, Nwariaku FE. Adrenal masses in the cancer patient: surveillance or excision. Oncologist 2007; 12:168-174.
67 Popescu I, Alexandrescu S, Ciurea S, et al. Adrenalectomy for metastases from hepatocellular carcinoma: a single center experience. Langenbecks Arch Surg 2007; 392:381-384.
68 Adler JT, Mack E, Chen H. Equal oncologic results for laparoscopic and open · resection of adrenal metastases. J Surg Res 2007; 140:159-164.
This study directly compares the results of nine patients who underwent laparo- scopic adrenalectomy with eight patients with open adrenalectomy in treatment of isolated adrenal metastasis and found that laparoscopic approach is a safe alternative with equal oncologic outcomes in patients without local invasion and smaller tumors.